U.S. patent application number 11/203899 was filed with the patent office on 2006-06-22 for therapeutic agent for overactive bladder involved in aging.
Invention is credited to Hironobu Akino, Masaharu Nakai, Osamu Yokoyama.
Application Number | 20060135507 11/203899 |
Document ID | / |
Family ID | 36596862 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060135507 |
Kind Code |
A1 |
Yokoyama; Osamu ; et
al. |
June 22, 2006 |
Therapeutic agent for overactive bladder involved in aging
Abstract
A method for treating overactive bladder involved in aging,
comprising administrating a compound having a cholinesterase
inhibitory activity, a pharmacologically acceptable salt or a
solvate thereof to a patient with the overactive bladder involved
in aging.
Inventors: |
Yokoyama; Osamu; (Fukui,
JP) ; Nakai; Masaharu; (Fukui, JP) ; Akino;
Hironobu; (Fukui, JP) |
Correspondence
Address: |
DICKSTEIN SHAPIRO MORIN & OSHINSKY LLP
1177 AVENUE OF THE AMERICAS (6TH AVENUE)
41 ST FL.
NEW YORK
NY
10036-2714
US
|
Family ID: |
36596862 |
Appl. No.: |
11/203899 |
Filed: |
August 15, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60601442 |
Aug 13, 2004 |
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Current U.S.
Class: |
514/214.01 ;
514/297; 514/319; 514/411 |
Current CPC
Class: |
A61K 31/407 20130101;
A61K 31/55 20130101; A61K 31/473 20130101; A61K 31/445
20130101 |
Class at
Publication: |
514/214.01 ;
514/319; 514/297; 514/411 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/473 20060101 A61K031/473; A61K 31/445 20060101
A61K031/445; A61K 31/407 20060101 A61K031/407 |
Claims
1. A method for treating overactive bladder involved in aging,
comprising administering a compound having a cholinesterase
inhibitory activity, a pharmacologically acceptable salt or a
solvate thereof to a patient with the overactive bladder involved
in aging.
2. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is a cyclic amine derivative
represented by the following general formula: ##STR83## (wherein, J
is: (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group; (b) a
monovalent or divalent group derived from a group selected from the
group consisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4)
indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8)
indanolyl, and (9) a group represented by formula ##STR84## in all
of which a phenyl group may be substituted; (c) a monovalent group
derived from a cyclic amide compound; (d) a lower alkyl group; or
(e) a group represented by formula R.sup.1--CH.dbd.CH-- (wherein
R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl group), B is a
group represented by formula ##STR85## a group represented by
formula ##STR86## a group represented by formula ##STR87##
(wherein, R.sup.3 is a hydrogen atom, a lower alkyl group, an acyl
group, a lower alkylsulfonyl group, a substituted or unsubstituted
phenyl group or a benzyl group), a group represented by formula
##STR88## (wherein, R.sup.4 is a hydrogen atom, a lower alkyl group
or a phenyl group), a group represented by formula ##STR89## a
group represented by formula ##STR90## a group represented by
formula ##STR91## a group represented by formula ##STR92## a group
represented by formula ##STR93## a group represented by formula
##STR94## a group represented by formula ##STR95## (wherein, n is 0
or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR96## a group
represented by formula ##STR97## a group represented by formula
##STR98## a group represented by formula ##STR99## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group, T
is a nitrogen atom or a carbon atom, Q is a nitrogen atom, a carbon
atom or a group represented by formula ##STR100## K is a hydrogen
atom, a substituted or unsubstituted phenyl group, an arylalkyl
group in which a phenyl group may be substituted, a cinnamyl group
in which a phenyl group may be substituted, a lower alkyl group, a
pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl
group, a furylmethyl group, a substituted or unsubstituted
cycloalkyl group, a lower alkoxycarbonyl group or an acyl group, q
is an integer of 1 to 3, and indicates a single bond or a double
bond).
3. A method according to claim 2, wherein J is a group selected
from the group consisting of: substituted or unsubstituted (1)
phenyl group, (2) pyridyl group, (3) pyradyl group, (4) quinolyl
group, (5) cyclohexyl group, (6) quinoxalyl group and (7) furyl
group.
4. A method according to claim 2, wherein J is a monovalent group
derived from a cyclic amide compound.
5. A method according to claim 1, wherein a compound having a
cholinesterase inhibitory activity is a cyclic amine derivatives
represented by the following general formula: ##STR101## (wherein,
J.sup.1 is a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, and (9) a group represented by
formula ##STR102## in all of which a phenyl group may be
substituted, B is a group represented by formula ##STR103## a group
represented by formula ##STR104## a group represented by formula
##STR105## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR106## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR107## a group represented by formula ##STR108## a group
represented by formula ##STR109## a group represented by formula
##STR110## a group represented by formula ##STR111## a group
represented by formula ##STR112## a group represented by formula
##STR113## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2
is a hydrogen atom or a methyl group), a group represented by
formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1
to 3), a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR114## a group
represented by formula ##STR115## a group represented by formula
##STR116## a group represented by formula ##STR117## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group, T
is a nitrogen atom or a carbon atom, Q is a nitrogen atom, a carbon
atom or a group represented by formula ##STR118## K is a hydrogen
atom, a substituted or unsubstituted phenyl group, an arylalkyl
group in which a phenyl group may be substituted, a cinnamyl group
in which a phenyl group may be substituted, a lower alkyl group, a
pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl
group, a furylmethyl group, a substituted or unsubstituted
cycloalkyl group, a lower alkoxycarbonyl group or an acyl group, q
is an integer of 1 to 3, and indicates a single bond or a double
bond).
6. A method according to claim 5, wherein B is a group represented
by formula ##STR119## (wherein n is 0 or an integer of 1 to 10, and
R.sup.2 is a hydrogen atom or a methyl group), a group represented
by formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an
integer of 1 to 10, R.sup.2 is a hydrogen atom or a methyl group),
a group represented by formula .dbd.(CH--CH.dbd.CH).sub.b--
(wherein, b is an integer of 1 to 3), a group represented by
formula .dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer
of 1 to 9) or a group represented by formula
.dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of 1 to
5).
7. A method according to claim 1, wherein a compound having a
cholinesterase inhibitory activity is a cyclic amine derivative
represented by the following general formula: ##STR120## (wherein,
J.sup.1 is a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, (9) a group represented by formula
##STR121## in all of which a phenyl group may be substituted,
B.sup.1 is a group represented by formula ##STR122## (wherein, n is
0 or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10, and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5), and K is a hydrogen
atom, a substituted or unsubstituted phenyl group, an arylalkyl
group in which a phenyl group may be substituted, a cinnamyl group
in which a phenyl group may be substituted, a lower alkyl group, a
pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl
group, a furylmethyl group, a substituted or unsubstituted
cycloalkyl group, a lower alkoxycarbonyl group or an acyl
group).
8. A method according to claim 7, wherein K is a substituted or
unsubstituted arylalkyl group or phenyl group.
9. A method according to either one of claims 7 and 8, wherein
J.sup.1 is a group selected from the group consisting of monovalent
and divalent groups derived from indanonyl, indenyl and
indanedionyl.
10. A method according to either one of claims 7 and 8, wherein
J.sup.1 is an indanonyl group which may contain, as a substituent,
a lower alkyl group with a carbon number 1 to 6 or a lower alkoxy
group with a carbon number 1 to 6.
11. A method according to claim 2, wherein the cyclic amine
derivative is at least one selected from the group consisting of:
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenylpiperidine,
and
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine.
12. A method according to claim 2, wherein the cyclic amine
derivative is
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
13. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl) methylpiperidine
hydrochloride.
14. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is galantamine, tacrine,
physostigmine or rivastigmine.
15. A process for screening a substance for suppressing overactive
bladder involved in aging, comprising: administering a compound
having a cholinesterase inhibitory activity, a pharmacologically
acceptable salt or a solvate thereof to a non-human mammal; and
detecting or determining a change in at least one selected from the
group consisting of a bladder capacity, a bladder contraction
pressure and an amount of retained urine, in the presence and
absence of the compound, the pharmacologically acceptable salt or
the solvate thereof.
16. A method according to claim 15, wherein the compound having a
cholinesterase inhibitory activity is a compound having an
acetylcholinesterase inhibitory activity, a pharmacologically
acceptable salt or a solvate thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an agent and a method for
treating overactive bladder involved in aging.
BACKGROUND OF THE INVENTION
[0002] Overactive bladder is a disease recently recognized by the
International Continence Society (ICS), whose major symptom being
urinary urgency, which may involve urinary frequency, sometimes
causing urinary incontinence. Drugs that can be used by urologists
at present for treating overactive bladder such as urinary urgency,
urinary frequency and urinary incontinence are limited to
anticholinergic agents (antimuscarinic agents). While
anticholinergic agents suppress bladder contractions via
acetylcholine (ACh), they are also associated with common side
effects such as dry mouth (salivation disorder) and constipation.
This is because a subtype of muscarine receptor (M3) in the bladder
commonly exist in the salivary gland and the gastrointestinal
tract. Therefore, patients with gastrointestinal tract obstruction
(such as ileus) cannot be administered with an anticholinergic
agent.
[0003] Overactive bladders are observed in 50-70% of the patients
with lower urinary tract obstruction such as prostatic hyperplasia,
and administration of anticholinergic agents may worsen their
drainage obstruction. Furthermore, anticholinergic agents are
mentioned of its transfer to the nerve center where it may possibly
damage higher brain functions (recognition, learning, emotion,
memory and sleep). From this viewpoint, drugs that rely on new
mechanism have been expected.
[0004] Overactive bladder is said to increase with age. Aging
deteriorates physical strength and functions of various organs as
well as bladder functions. For example, deterioration of
acetylcholine (ACh) nerve function of central nerve system (e.g.,
decrease in ACh release, decrease in the number of muscarine
receptors, deterioration of ACh-associated enzyme) associated with
aging have been reported. We have investigated how this
deterioration of ACh nerve functions is related to increased
micturition reflex, namely overactive bladder observed in elderly
people. As a result, we considered that ACh system that projects to
the cerebral cortex from the forebrain basal ganglia projects
suppressively to the micturition reflex center, and since this
projecting system is antagonized by pirenzepine, i.e., a muscarine
M1 receptor blocking agent, overactive bladder is mediated by
muscarine M1 receptor (Yokoyama O, Ootsuka N, Komatsu K, Kodama K,
Yotsuyanagi S, Niikura S, Nagasaka Y, Nakada Y, Kanie S, Namiki M:
Forebrain muscarinic control of micturition reflex in rats.
Neuropharmocology 41:629-638, 2001). When Aniracetam that
stimulates ACh release in the brain is administered to a rat or
human with overactive bladder caused by cerebrovascular disease,
suppression of micturition reflex is observed (Nakada Y, Yokoyam O,
Kamatsu K, Kodama K, Yotsuyanagi S, Niikura S, Nagasaka Y and
Namiki M: Effects of aniracetam on bladder overactivity in rats
with cerebral infarction. J Pharmacol Exp Ther 293: 921-928, 2000,
and Osamu Yokoyama: Micturition Disorder, From Basic Research to
Clinical Application, Journal of Japanese Urological Association
91: 140, 2000), which suggests that activation of ACh system in the
brain may possibly improve overactive bladder.
[0005] On the other hand, as therapeutic agents for lower urinary
tract disorder, several compounds with acetylcholinesterase
inhibitory activities have been reported. Lower urinary tract
disease can be classified into micturition disorders and urine
collection disorders. As one of the therapeutic agents for the
former disorders, a non-carbamate amine compound with an
acetylcholinesterase inhibitory activity has been reported
(International Patent Publication No. 00/18391 pamphlet). However,
as to the latter case, i.e., urine collection disorders involved in
the overactive bladder such as urinary urgency, urinary frequency
and urinary incontinence, no disclosure or suggestion has been
made.
[0006] Donepezil hydrochloride is a substance that reversibly
inhibits acetylcholinesterase, i.e., an acetylcholine-degrading
enzyme, which increases the amount of acetylcholine in the brain
and activates cholinergic nervous system in the brain. This
substance is extensively used as therapeutic agents for senile
dementia of Alzheimer type and Alzheimer's disease (Japanese Patent
No. 2578475). However, whether this centrally-active
acetylcholinesterase inhibitor, donepezil hydrochloride, has effect
on urine collection disorder associated with overactive bladder
such as urinary urgency, urinary frequency and urinary incontinence
involved in aging has not been confirmed.
SUMMARY OF THE INVENTION
[0007] The present invention provides a drug effective in treating
urine collection disorder associated with overactive bladder
involved in aging having symptoms such as urinary urgency, urinary
frequency and urinary incontinence.
[0008] As a result of devoting studies on the above-described
problems, we found that when donepezil hydrochloride that inhibits
acetylcholinesterase in the brain and that increases acetylcholine
(ACh) in the brain was administered to rats, micturition reflex was
suppressed to a higher degree in 10-month-old rats than the 3- and
10-week-old rats upon the donepezil hydrochloride administration.
This result suggests that donepezil hydrochloride activates ACh
system in the brain and possibly ameliorates overactive bladder
involved in aging. Based on these findings, we completed the
present invention.
[0009] Thus, the present invention provides the followings.
[0010] (1) A method for treating overactive bladder involved in
aging, comprising administrating a compound having a cholinesterase
inhibitory activity, a pharmacologically acceptable salt or a
solvate thereof to a patient with the overactive bladder involved
in aging.
[0011] An example of a compound having a cholinesterase inhibitory
activity used in the method of the present invention includes a
cyclic amine derivatives represented by the following general
formula: ##STR1## (wherein, J is:
[0012] (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group;
[0013] (b) a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, or (9) a group represented by formula
##STR2## in all of which a phenyl group may be substituted;
[0014] (c) a monovalent group derived from a cyclic amide
compound;
[0015] (d) a lower alkyl group; or
[0016] (e) a group represented by formula R.sup.1--CH.dbd.CH--
(wherein R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl
group),
[0017] B is a group represented by formula ##STR3## a group
represented by formula ##STR4## a group represented by formula
##STR5## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl group,
an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR6## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR7## a group represented by formula ##STR8## a group
represented by formula ##STR9## a group represented by formula
##STR10## a group represented by formula ##STR11## a group
represented by formula ##STR12## a group represented by formula
##STR13## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR14## a group
represented by formula ##STR15## a group represented by formula
##STR16## a group represented by formula ##STR17## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0018] T is a nitrogen atom or a carbon atom,
[0019] Q is a nitrogen atom, a carbon atom or a group represented
by formula ##STR18##
[0020] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0021] q is an integer of 1 to 3, and
[0022] indicates a single bond or a double bond).
[0023] Specifically, said J may be a group selected from the group
consisting of substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group and (7) furyl group.
Furthermore, said J may be a monovalent group derived from a cyclic
amide compound.
[0024] The compound having a cholinesterase inhibitory activity
described above may be a cyclic amine derivative represented by the
following general formula: ##STR19## (wherein, J.sup.1 is a
monovalent or divalent group derived from a group selected from the
group consisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4)
indenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl,
(8) indanolyl and (9) a group represented by formula ##STR20## in
all of which a phenyl group may be substituted,
[0025] B is a group represented by formula ##STR21## a group
represented by formula ##STR22## a group represented by formula
##STR23## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR24## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR25## a group represented by formula ##STR26## a group
represented by formula ##STR27## a group represented by formula
##STR28## a group represented by formula ##STR29## a group
represented by formula ##STR30## a group represented by formula
##STR31## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR32## a group
represented by formula ##STR33## a group represented by formula
##STR34## a group represented by formula ##STR35## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0026] T is a nitrogen atom or a carbon atom,
[0027] Q is a nitrogen atom, a carbon atom or a group represented
by formula ##STR36##
[0028] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0029] q is an integer of 1 to 3, and
[0030] indicates a single bond or a double bond).
[0031] Specifically, B may be a group represented by formula
##STR37## (wherein, n is 0 or an integer of 1 to 10 and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10 and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5).
[0032] Furthermore, the compound having the cholinesterase
inhibitory activity described above may be a cyclic amine
derivative represented by the following general formula: ##STR38##
(wherein, J.sup.1 is a monovalent or divalent group derived from a
group selected from the group consisting of (1) indanyl, (2)
indanonyl, (3) indenyl, (4) indenonyl, (5) indandionyl, (6)
tetralonyl, (7) benzsuberonyl, (8) indanolyl and (9) a group
represented by formula ##STR39## in all of which a phenyl group may
be substituted,
[0033] B.sup.1 is a group represented by formula ##STR40##
(wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is a
hydrogen atom or a methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10 and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5), and
[0034] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group).
[0035] Specifically, said K may be a substituted or unsubstituted
arylalkyl group or phenyl group, and said J.sup.1 may be a group
selected from the group consisting of monovalent groups and
divalent groups derived from indanonyl, indenyl and indandionyl.
Furthermore, an example of J.sup.1 includes an indanonyl group
which may have as a substituent a lower alkyl group with a carbon
number 1 to 6 or a lower alkoxy group with a carbon number 1 to
6.
[0036] The above-mentioned cyclic amine derivative may be at least
one selected from the group consisting of: [0037]
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenylpiperidine,
and
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine,
or may be
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
According to the present invention, a compound with a
cholinesterase inhibitory activity is preferably
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine
hydrochloride.
[0038] The compound having an acetylcholinesterase inhibitory
activity described above may be galantamine, tacrine, physostigmine
or rivastigmine.
[0039] (2) A process for screening a substance for suppressing
overactive bladder involved in aging, comprising: administering a
candidate substance to a non-human mammal; and detecting or
determining a change in a phenotype of the overactive bladder
involved in aging in the presence and absence of the candidate
substance.
[0040] For the screening process of the present invention, the
candidate substance include, for example, a compound having a
cholinesterase inhibitory activity, a pharmacologically acceptable
salt or a solvate thereof. Herein, the change in the phenotype of
overactive bladder involved in aging can use as an index at least
one selected from the group consisting of a bladder capacity, a
bladder contraction pressure and an amount of retained urine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 shows effects of donepezil hydrochloride on bladder
capacities of 3-week, 10-week and 10-month old rats;
[0042] FIG. 2 shows the change in the curve of pressure within the
bladder when donepezil hydrochloride is intraventiricularly
administered;
[0043] FIG. 3 shows a percentage of change in bladder capacity;
and
[0044] FIG. 4 shows a percentage of change in micturition
contraction pressure.
DETAILED DESCRIPTION OF THE INVENTION
[0045] Hereinafter, embodiments of the present invention will be
described. The following embodiments are merely meant to illustrate
the present invention and the present invention is not limited
thereto. The present invention may be carried out in various
embodiment without departing from the scope of the invention.
[0046] All references, laid-open applications, patent publications
and the like cited in this specification are herein incorporated by
reference.
[0047] The present invention was accomplished by finding mechanisms
that a cholinesterase (ChE) inhibitor suppresses degradation of
acetylcholine and that increase in the concentration of
acetylcholine in the synaptic cleft ameliorates overactive bladder
involved in aging.
[0048] Thus, the present invention provides a therapeutic agent and
a therapeutic method for overactive bladder involved in aging
comprising as an active ingredient a compound having an action of
suppressing the acetylcholine degradation and increasing the
acetylcholine concentration, i.e., a compound with a cholinesterase
inhibitory activity, a pharmacologically acceptable salt or a
solvate thereof.
[0049] 1. Compound with Cholinesterase (ChE) Inhibitory
Activity
[0050] According to the present invention, an active substance for
treating overactive bladder involved in aging comprises a compound
with a ChE inhibitory activity, a pharmacologically acceptable salt
or a solvate thereof. The compound with a ChE inhibitory activity
according to the present invention refers to a substance with a ChE
inhibitory activity, i.e., a substance that reversibly or
irreversibly inhibits a ChE activity. In the present invention, ChE
comprises acetylcholinesterase (AChE) (EC3.1.1.7),
butyrylcholinesterase or the like. Preferable features of the
compound with a ChE inhibitory activity of the present invention
include that it is highly selective for AChE over
butyrylcholinesterase, it effects centrally, it is capable of
passing through the blood-brain barrier, and it does not cause
severe side effect at a dose required for treatment.
[0051] According to the present invention, a preferable compound
used as a therapeutic agent for overactive bladder involved in
aging comprises a compound with a ChE, particularly AChE inhibitory
activity. This compound comprises a pharmacologically acceptable
salt of the compound with a ChE inhibitory activity, a solvate
thereof and a prodrug thereof as described below.
[0052] (1) Compound with Cholinesterase Inhibitory Activity
[0053] According to the present invention, compounds with a ChE
inhibitory activity include donepezil (ARICEPT.RTM.), galantamine
(Reminyl.RTM.), tacrine (Cognex.RTM.), rivastigmine (Exelon.RTM.),
zifrosilone (U.S. Pat. No. 5,693,668 specification), physostigmine
(Synapton) (Neurobiology of Aging 26 (2005) 939-946), ipidacrine
(U.S. Pat. No. 4,550,113 specification), quilostigmine, metrifonate
(Promem) (U.S. Pat. No. 4,950,658 specification), eptastigmine,
velnacrine, tolserine, cymserine (U.S. Pat. No. 6,410,747
specification), mestinon, icopezil (U.S. Pat. No. 5,750,542
specification), TAK-147 (J. Med. Chem., 37(15), 2292-2299, 1994,
Japanese Patent Publication No. 2650537, U.S. Pat. No. 5,273,974
specification), huperzine A (Drugs Fut. , 24, 647-663, 1999),
stacofylline (U.S. Pat. No. 4,599,338 specification),
thiatolserine, neostigmine, eseroline or thiacymserine,
8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetr-
ahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (Japanese Patent
Publication No.3512786), phenserine or ZT-1. The compound may also
be a derivative or a prodrug of the above compounds. In addition, a
pharmacologically acceptable salt or a solvate of the above
compounds, derivatives and prodrugs may also be included as
preferred embodiments of the compound with a ChE inhibitory
activity. The compound with a ChE inhibitory activity also includes
the compound with a ChE inhibitory activity described in
International Patent Publication No.00/18391 pamphlet.
[0054] Galantamine and derivatives thereof are described in U.S.
Pat. No. 4,663,318 specification, International Patent Publication
No.88/08708 pamphlet, International Patent Publication No.97/03987
pamphlet, U.S. Pat. No. 6,316,439 specification, U.S. Pat. No.
6,323,195 specification, U.S. Pat. No. 6,323,196 specification and
the like. Tacrine and derivatives thereof are described in U.S.
Pat. No. 4,631,286 specification, U.S. Pat. No. 4,695,573
specification, U.S. Pat. No. 4,754,050 specification, International
Patent Publication No.88/02256 pamphlet, U.S. Pat. No. 4,835,275
specification, U.S. Pat. No. 4,839,364 specification, U.S. Pat. No.
4,999,430 specification, International Patent Publication
WO97/21681 pamphlet and the like. Physostigmine and derivatives
thereof are described in U.S. Pat. No. 5,077,289 specification,
U.S. Pat. No. 5,177,101 specification, U.S. Pat. No. 5,302,721
specification, Japanese Laid-Open Application No. 5-306286, U.S.
Pat. No. 7,166,824 specification, EP Patent No.298202
specification, International Patent Publication No.98/27096
pamphlet, J. Pharm. Exp. Therap., 249 (1), 194-202, 1989 and the
like. Rivastigmine and derivatives thereof are described in EP
Patent No. 193926 specification, International Patent Publication
No.98/26775 pamphlet, International Patent Publication No.98/27055
pamphlet and the like.
[0055] "Prodrug" as used herein means a drug obtained by chemically
modifying "an active principle of a drug" (i.e., a "drug"
corresponding to the prodrug) into an inactive substance for the
purpose of bioavailability improvement, alleviation of side effects
or the like, which, after absorption, is metabolized to an active
principle in the body and exerts action. Thus, the term "prodrug"
refers to any compound that has a lower intrinsic activity than a
corresponding "drug" but which, when administered to a biological
system, generates the "drug" substance as a result of spontaneous
chemical reaction, enzyme catalysis or metabolic reaction. Examples
of such prodrugs include those in which an amino group, a hydroxyl
group or a carboxyl group of the above-exemplified compound or a
compound represented by the general formula below has been
acylated, alkylated, phosphorylated, borated, carbonated,
esterified, amidated or urethanated. This exemplified group,
however, merely represents typical examples and thus is not
comprehensive. Those skilled in the art can prepare other various
known prodrugs from the above-exemplified compound or the compound
represented by the general formula below according to a known
method. A prodrug comprising the above-exemplified compound or the
compound represented by the general formula below is within the
scope of the invention.
[0056] (2) Cyclic Amine Derivatives
[0057] According to the present invention, preferred examples of a
compound with a ChE inhibitory activity, specifically an ACHE
inhibitory activity further include a cyclic amine derivative
represented by the following general formula (I), a
pharmacologically acceptable salt and a solvate thereof. According
to the present invention, a compound with a ChE inhibitory activity
is preferably
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
(donepezil), a pharmacologically acceptable salt or a solvate
thereof, more preferably
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride (donepezil hydrochloride), i.e., ARICEPT.RTM..
[0058] General Formula (I) ##STR41## (wherein, J refers to one
selected from groups (a) to (e) listed below:
[0059] (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group;
[0060] (b) a monovalent or divalent group derived from one selected
from the group consisting of (1) indanyl, (2) indanonyl, (3)
indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, and (9) a group represented by
formula ##STR42## in all of which a phenyl group may be
substituted,
[0061] (c) a monovalent group derived from a cyclic amide
compound,
[0062] (d) a lower alkyl group, or
[0063] (e) a group represented by formula R.sup.1--CH.dbd.CH--
(wherein, R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl
group),
[0064] B refers to a group represented by formula ##STR43## a group
represented by formula ##STR44## a group represented by formula
##STR45## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR46## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR47## a group represented by formula ##STR48## a group
represented by formula ##STR49## a group represented by formula
##STR50## a group represented by formula ##STR51## group
represented by formula ##STR52## a group represented by formula
##STR53## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR54## a group
represented by formula ##STR55## a group represented by formula
##STR56## a group represented by formula ##STR57## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0065] T represents a nitrogen atom or a carbon atom,
[0066] Q represents a nitrogen atom, a carbon atom or a group
represented by formula ##STR58##
[0067] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0068] q is an integer of 1 to 3, and
[0069] indicates a single bond or a double bond).
[0070] "A lower alkyl group" as used herein comprises a straight or
branched alkyl group with a carbon number 1 to 6, for example, a
methyl group, an ethyl group, an n-propyl group, an isopropyl
group, an n-butyl group, an isobutyl group, a sec-butyl group, a
tert-butyl group, a pentyl group (an amyl group), an isopentyl
group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl
group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl
group, an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl
group, a 3-methylpentyl group, a 1,1-dimethylbutyl group, a
1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a
1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a
3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl
group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl
group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl
group and the like. Preferable groups among them include a methyl
group, an ethyl group, a propyl group and an isopropyl group, most
preferable group being a methyl group. "A lower alkyl group" is
described in the definition of the above compound (I) of the
present invention, for example, in the definitions of J, K, R.sup.3
and R.sup.4.
[0071] "A lower alkoxy group" as used herein means a lower alkoxy
group corresponding to the above-mentioned lower alkyl group such
as a methoxy group and an ethoxy group.
[0072] "A lower alkoxycarbonyl group" as used herein means a lower
alkoxycarbonyl group corresponding to the above-mentioned lower
alkoxy group such as a methoxycarbonyl group, an ethoxycarbonyl
group, an isopropoxycarbonyl group, an n-propoxycarbonyl group and
an n-butyloxycarbonyl group.
[0073] "A cycloalkyl group" as used herein refers to a cyclic alkyl
group with a carbon number 4 to 10, including but not limited to a
cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
[0074] "J"
[0075] In the definition of J, exemplary substituents for "(a)
substituted or unsubstituted (1) phenyl group, (2) pyridyl group,
(3) pyradyl group, (4) quinolyl group, (5) cyclohexyl group, (6)
quinoxalyl group or (7) furyl group" include:
[0076] a lower alkyl group with a carbon number 1 to 6 such as a
methyl group, an ethyl group, an n-propyl group, an isopropyl
group, an n-butyl group, an isobutyl group and a tert-butyl
group;
[0077] a lower alkoxy group corresponding to a lower alkyl group
such as a methoxy group and an ethoxy group;
[0078] a nitro group;
[0079] a halogen such as chlorine, bromine and fluorine;
[0080] a carboxyl group;
[0081] a lower alkoxycarbonyl group corresponding to the lower
alkoxy group above such as a methoxycarbonyl group, an
ethoxycarbonyl group, an isopropoxycarbonyl group, an
n-propoxycarbonyl group and an n-butyloxycarbonyl group;
[0082] an amino group;
[0083] a mono-lower alkylamino group;
[0084] a di-lower alkylamino group;
[0085] a carbamoyl group;
[0086] an acylamino group derived from aliphatic saturated
monocarboxylic acid with a carbon number 1 to 6 such as an
acetylamino group, a propionylamino group, a butyrylamino group, an
isobutyrylamino group, a valerylamino group and a pivaloyl amino
group;
[0087] a cycloalkyloxycarbonyl group such as a
cyclohexyloxycarbonyl group;
[0088] a lower alkylaminocarbonyl group such as a
methylaminocarbonyl group and an ethylaminocarbonyl group;
[0089] a lower alkylcarbonyloxy group corresponding to the lower
alkyl group defined above such as a methylcarbonyloxy group, an
ethylcarbonyloxy group and an n-propylcarbonyloxy group;
[0090] a halogenated lower alkyl group as represented by a
trifluoromethyl group or the like;
[0091] a hydroxyl group;
[0092] a formyl group; and
[0093] a lower alkoxy lower alkyl group such as an ethoxymethyl
group, a methoxymethyl group and a methoxyethyl group. As to the
above substituents, "the lower alkyl group" and "the lower alkoxy
group" comprise all of the groups that can be derived from the
definition described above. Groups (1) to (7) from (a) may be
substituted with 1 to 3 of the same or different substituents
mentioned above.
[0094] In the case of the phenyl group, the following case is also
to be included in the substituted phenyl group: that is, when a
group can be represented by formula ##STR59## (wherein, G is a
group represented by ##STR60## a group represented by ##STR61##
group represented by --O--, a group represented by ##STR62## a
group represented by --CH.sub.2--O--, a group represented by
--CH.sub.2--SO.sub.2--, a group represented by ##STR63## or a group
represented by ##STR64## and
[0095] E represents a carbon atom or a nitrogen atom).
[0096] D may represent a lower alkyl group with a carbon number 1
to 6 such as a methyl group, an ethyl group, an n-propyl group, an
isopropyl group, an n-butyl group, an isobutyl group, and a
tert-butyl group;
[0097] a lower alkoxy group corresponding to the lower alkyl group
above such as a methoxy group and an ethoxy group;
[0098] a nitro group;
[0099] a halogen such as chlorine, bromine and fluorine;
[0100] a carboxyl group;
[0101] a lower alkoxycarbonyl group corresponding to the lower
alkoxy group above such as a methoxycarbonyl group, an
ethoxycarbonyl group, an isopropoxycarbonyl group, an
n-propoxycarbonyl group and an n-butyloxycarbonyl group;
[0102] an amino group;
[0103] a mono-lower amino group;
[0104] a di-lower alkylamino group;
[0105] a carbamoyl group;
[0106] an acylamino group derived from aliphatic saturated
monocarboxylic acid with a carbon number 1 to 6 such as an
acetylamino group, a propionylamino group, a butyrylamino group, an
isobutyrylamino group, a valerylamino group and a pivaloylamino
group;
[0107] a cycloalkyloxycarbonyl group such as a
cyclohexyloxycarbonyl group;
[0108] a lower alkylaminocarbonyl group such as a
methylaminocarbonyl group and an ethylaminocarbonyl group;
[0109] a lower alkylcarbonyloxy group corresponding to the lower
alkyl group defined above such as a methylcarbonyloxy group, an
ethylcarbonyloxy group and an n-propylcarbonyloxy group;
[0110] a halogenated lower alkyl group as represented by a
trifluoromethyl group;
[0111] a hydroxyl group;
[0112] a formyl group;
[0113] a lower alkoxy lower alkyl group such as an ethoxymethyl
group, a methoxymethyl group and a methoxyethyl group.
[0114] As to the substituents, "the lower alkyl group" and "the
lower alkoxy group" comprise all of the groups that can be derived
from the definition described above.
[0115] Among those mentioned above, substituents favorable for a
phenyl group include a lower alkyl group, a lower alkoxy group, a
nitro group, a halogenated lower alkyl group, a lower
alkoxycarbonyl group, a formyl group, a hydroxyl group, a lower
alkoxy lower alkyl group, a halogen, a benzoyl group and a
benzylsulfonyl group. The substituents may be two or more and may
be the same or different.
[0116] Preferred substituents for a pyridyl group may include a
lower alkyl group, an amino group and a halogen atom.
[0117] Preferred substituents for a pyradyl group may include a
lower alkoxycarbonyl group, a carboxyl group, an acylamino group, a
carbamoyl group and a cycloalkyloxycarbonyl group.
[0118] When representing "J", 2-pyridyl group, 3-pyridyl group or
4-pyridyl group is desirable as a pyridyl group, 2-pyradyl group is
desirable as a pyradyl group, 2-quinolyl group or 3-quinolyl group
is desirable as a quinolyl group, 2-quinoxalyl group or
3-quinoxalyl group is desirable as a quinoxalyl group, and 2-furyl
group is desirable as a furyl group.
[0119] In the definition of "J", typical examples of the monovalent
or divalent group derived from (1) to (9) listed in group (b) are
shown below: ##STR65##
[0120] In the above series of formulae, t means 0 or an integer of
1 to 4, indicating that the phenyl group is substituted by 0 to 4
groups indicated by S which may be the same or 5 different. S
identically or differently indicates one of the substituents listed
in (a) in the definition of J or a hydrogen atom and preferably
includes a hydrogen atom (unsubstituted), a lower alkyl group or a
lower alkoxy group. Furthermore, the phenyl group may be
substituted by an alkylenedioxy group such as a methylenedioxy
group or an ethylenedioxy group between adjacent carbons of the
phenyl ring.
[0121] Among those mentioned above, a preferable case is where no
substitution exist, where 1 to 3 methoxy groups or isopropoxy
groups are substituted, or where a methylenedioxy group is
substituted. Most preferable case is where no substitution exist,
or where 1 to 3 methoxy groups are substituted.
[0122] The above-mentioned indanolydenyl is an example where a
divalent group in which a phenyl group listed in (b) in the
definition of J may be substituted, i.e., a typical divalent group
derived from (2) indanonyl in J (b).
[0123] In the definition of J, examples of the monovalent group
derived from a cyclic amide compound from (c) include, for example,
quinazolone, tetrahydroisoquinoline-one,
tetrahydrobenzodiazepine-one and hexahydrobenzazocin-one, but are
not limited thereto as long as a cyclic amide exists in the
structural formula.
[0124] The cyclic amide may be derived from a monocyclic ring or a
condensed heterocyclic ring. Preferably, the condensed heterocyclic
ring is a condensed heterocyclic ring with a phenyl ring. In this
case, the phenyl ring may be substituted with a lower alkyl group
with a carbon number 1 to 6, preferably a methyl group, a lower
alkoxy group with a carbon number 1 to 6, preferably a methoxy
group or a halogen atom.
[0125] Preferable examples include the following: ##STR66##
##STR67## (wherein, Y in formulae (i) and (l) represents a hydrogen
atom or a lower alkyl group, V in formula (k) represents a hydrogen
atom or a lower alkoxy group, W.sup.1 and W.sup.2 in formulae (m)
and (n) each independently represent, identically or differently, a
hydrogen atom, a lower alkyl group or a lower alkoxy group, and
W.sup.3 is a hydrogen atom or a lower alkyl group. U in formula (j)
represents a hydrogen atom, a lower alkyl group or a lower alkoxy
group.
[0126] The rings on the right side in formulae (j) and (l) are
seven-membered rings, and the ring on the right side in formula (k)
is an eight-membered ring.
[0127] For the definition of J, "(d) a lower alkyl group" is as
described above.
[0128] Among those included in the above definition of J, groups
included in (a) to (c) are preferable, most preferable group being
a monovalent group derived from indanone (indanonyl) included in
(b) where a phenyl ring may be substituted or unsubstituted, and a
monovalent group derived from a cyclic amide compound included in
(c).
[0129] "B"
[0130] For the definition of B, a group represented by formula:
##STR68## is indicated as formula --(CH.sub.2).sub.n-- when R.sup.2
is a hydrogen atom. In this case, any of the carbon atoms of the
alkylene chain may further bind to one or more methyl groups and n
is preferably 1 to 3.
[0131] In B, examples of "dialkylaminoalkylcarbonyl group" include,
for example, N,N-dimethylaminoalkylcarbonyl group,
N,N-diethylaminoalkylcarbonyl group,
N,N-diisopropylaminoalkylcarbonyl group, and
N-methyl-N-ethylaminoalkylcarbonyl group.
[0132] As to a series of groups of B, a group including an amide
group is also preferable.
[0133] Examples of preferable groups further include a group
represented by formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n
is 0 or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d represents 0 or an
integer of 1 to 5), a group represented by formula --NH--, a group
represented by formula --O-- and a group represented by formula
--S--.
[0134] "T", "Q" and "q"
[0135] A ring ##STR69## may be a five- to seven-membered ring.
Specifically, examples of such ring include ##STR70## although
particularly preferable ring is piperidine represented by formula
##STR71##
[0136] "K" and "bonds"
[0137] As to expressions "substituted or unsubstituted phenyl
group", "substituted or unsubstituted arylalkyl group (where a
phenyl group may be substituted)", "cinnamyl group where a phenyl
group may be substituted", and "cycloalkyl group which may be
substituted" in the definition of K, the substituents are the same
as those defined in definition of J for (a) (1) to (7). These are
preferably unsubstituted or may be substituted with a nitro group,
a lower alkyl group such as methyl or a halogen such as
fluorine.
[0138] An arylalkyl group is intended to mean a benzyl group or a
phenetyl group in which a phenyl ring is substituted with a
substituent described above or unsubstituted.
[0139] Examples of pyridylmethyl group may specifically include
2-pyridylmethyl group, 3-pyridylmethyl group and 4-pyridylmethyl
group.
[0140] As to K, an arylalkyl group where a phenyl group may be
substituted, a substituted or unsubstituted phenyl group, a
cinnamyl group where a phenyl group may be substituted and a
cycloalkyl group which may be substituted are most preferable.
[0141] Preferable arylalkyl group is specifically, for example, a
benzyl group or a phenetyl group in which a phenyl group may be
substituted with a lower alkoxy group having a carbon number 1 to
6, a lower alkyl group having a carbon number 1 to 6, a hydroxyl
group or the like.
[0142] indicates a single bond or a double bond. An exemplary case
of the double bond includes the above-described divalent group
derived from indanone where a phenyl ring may be substituted,
namely an indanolydenyl group.
[0143] Compound Group (A)
[0144] Gathering from these definitions, particularly preferable
compound group include compound group (A) represented by the
following general formula, i.e., a cyclic amine represented by
formula: ##STR72## (wherein, J.sup.1 is a monovalent or divalent
group derived from a group selected from the group consisting of:
[0145] (1) indanyl, [0146] (2) indanonyl, [0147] (3) indenyl,
[0148] (4) indenonyl, [0149] (5) indandionyl, [0150] (6)
tetralonyl, [0151] (7) benzsuberonyl, [0152] (8) indanolyl, and
[0153] (9) a group represented by formula ##STR73## in all of which
a phenyl group may be substituted; and
[0154] B, T, Q, q, K and have the same meaning as described above),
a pharmacologically acceptable salt or a solvate thereof.
[0155] In the above definition of J.sup.1, the most preferable
groups include an indanonyl group, an indandionyl group and
indanolydenyl group where a phenyl group may be substituted.
Specifically, a phenyl group may be unsubstituted or substituted
identically or differently with a hydroxyl group, a halogen or a
lower alkoxy group, and most preferably substituted with an
alkylenedioxy group between adjacent carbon atoms of a phenyl ring.
A lower alkoxy group refers to, for example, a methoxy group, an
ethoxy group, an isopropoxy group, an n-propoxy group and an
n-butoxy group with a carbon number 1 to 6, and can take a form of
mono- to tetra-substitution, preferably disubstitution.
Disubstitution of the methoxy group is most preferable.
[0156] Compound Group (B)
[0157] More preferable compound group included in formula (A)
include a compound group represented by the following general
formula (B): ##STR74## (wherein, J.sup.1 is the same as described
above,
[0158] B.sup.1 is a group represented by ##STR75## (wherein, n is 0
or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n represents 0 or an
integer of 1 to 10, and R2 represents a hydrogen atom or a methyl
group), a group represented by formula .dbd.(CH--CH.dbd.CH).sub.b--
(wherein, b is an integer of 1 to 3), a group represented by
formula .dbd.CH--(CH.sub.2).sub.c-- (wherein, c represents 0 or an
integer of 1 to 9) or a group represented by formula
.dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of 1 to 5):
Preferably, B.sup.1 is a group represented by formula
--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of 1 to 10,
and R.sup.2 is a hydrogen atom or a methyl group), more preferably
--CH.sub.2-- (wherein, n=1, and R.sup.2 is a hydrogen atom), or
--CH.sub.2--CH.sub.2--CH.sub.2-- (wherein, n=3, and R.sup.2 is a
hydrogen atom): B.sup.1 is preferably a group represented by
formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an
integer of 1 to 10, and R.sup.2 is a hydrogen atom or a methyl
group), more preferably --CH.dbd.CH--CH.sub.2-- (wherein, n=1 and
R.sup.2 is a hydrogen atom), and
[0159] T, Q, q, K and are as described above).
[0160] Compound Group (C)
[0161] More preferable compound group included in formula (B) may
include a compound group represented by the following general
formula (C): ##STR76## (wherein, J.sup.1, B.sup.1, K and are as
described above).
[0162] Specifically, the group represented by formula ##STR77## is
indicated by a group represented by formula ##STR78## i.e.,
piperidine.
[0163] Compound Group (D)
[0164] More preferable compound group included in formula (C) may
include a compound group represented by the following general
formula (D): ##STR79## (wherein, J.sup.2 is a group selected from a
monovalent or divalent group derived from indanonyl where a phenyl
group may be substituted (e.g., indanonyl, indanolydenyl group),
indenyl and indandionyl: More preferably, J.sup.2 is an indanonyl
group which may 10 have, as a substituent, a lower alkyl group with
a carbon number 1 to 6 or a lower alkoxy group with a carbon number
1 to 6,
[0165] K.sup.1 is a substituted or unsubstituted phenyl group, an
arylalkyl group which may be substituted, a cinnamyl group which
may be substituted or a cycloalkyl group which may be substituted,
and B.sup.1 and are as described above).
[0166] Moreover, a particularly preferable compound group (a
compound group having a ChE inhibitory activity) of cyclic amine
derivatives represented by general formula (I) or pharmacologically
acceptable salts thereof includes the following: [0167]
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenyl)piperidine,
and
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine,
more preferably
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
[0168] (3) Production Process
[0169] A compound having a ChE inhibitory activity, a
pharmacologically acceptable salt thereof or a solvate thereof used
in the present invention can be produced according to a known
method. The cyclic amine derivatives represented by the general
formula (I) above (e.g., donepezil hydrochloride) can readily be
produced by methods disclosed, as representative examples, in
Japanese Laid-Open Application No. 1-79151, Japanese Patent
Publication No. 2578475, Japanese Patent Publication No. 2733203,
Japanese Patent Publication No. 3078244 or U.S. Pat. No. 4,895,841.
Donepezil hydrochloride is also available as a formulation such as
fine granules.
[0170] Galantamine and derivatives thereof can readily be produced
by methods disclosed, for example, in U.S. Pat. No. 4,663,318
specification, International Patent Publication No.88/08708
pamphlet, International Patent Publication No.97/03987 pamphlet,
U.S. Pat. No. 6,316,439 specification, U.S. Pat. No. 6,323,195
specification and U.S. Pat. No. 6,323,196 specification.
[0171] Tacrine and derivatives thereof can readily be produced by
methods disclosed, for example, in U.S. Pat. No. 4,631,286
specification, U.S. Pat. No. 4,695,573 specification, U.S. Pat. No.
4,754,050 specification, International Patent Publication
No.88/02256 pamphlet, U.S. Pat. No. 4,835,275 specification, U.S.
Pat. No. 4,839,364 specification, U.S. Pat. No. 4,999,430
specification, and International Patent Publication WO97/21681
pamphlet.
[0172] Physostigmine and derivatives thereof can readily be
produced by methods disclosed, for example, in U.S. Pat. No.
5,077,289 specification, U.S. Pat. No. 5,177,101 specification,
U.S. Pat. No. 5,302,721 specification, Japanese Laid-Open
Application No.5-306286, U.S. Pat. No. 7,166,824 specification, EP
Patent No. 298202 specification, International Patent Publication
No.98/27096 pamphlet, and J. Pharm. Exp. Therap., 249 (1), 194-202,
1989.
[0173] Rivastigmine and derivatives thereof can readily be produced
by methods disclosed, for example, in EP Patent No. 193926
specification, International Patent Publication No.98/26775
pamphlet, and International Patent Publication No. 98/27055
pamphlet.
[0174] Among these compounds, those that are commercially available
can readily be obtained from, for example, chemical
manufacturers.
[0175] According to the present invention, examples of
pharmacologically acceptable salts include, for example, inorganic
acid salts such as hydrochloride, sulfate, hydrobromate and
phosphate, or organic acid salts such as formate, acetate,
trifluoroacetate, maleate, tartrate, methanesulfonate,
benzenesulfonate and toluenesulfonate.
[0176] In addition, depending on the choice of the substituent, for
example, alkali metal salts such as sodium salt and potassium salt,
alkaline earth metal salts such as calcium salt and magnesium salt,
organic amine salts such as trimethylamine salt, triethylamine
salt, pyridine salt, picoline salt, dicyclohexylamine salt and
N,N'-dibenzylethylenediamine salt, and ammonium salt are
formed.
[0177] According to the present invention, a compound having a ChE
inhibitory activity or a pharmacologically acceptable salt thereof
(e.g., donepezil hydrochloride) as an active ingredient for
overactive bladder treatment may be an anhydride, and may form a
solvate such as a hydrate. According to the present invention, a
solvate is preferably a pharmacologically acceptable solvate. A
pharmacologically acceptable solvate may be either a hydrate or a
nonhydrate, but preferably a hydrate. A solvent such as water,
alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide,
dimethyl sulfoxide (DMSO) or the like may be used. For example,
crystal polymorph may exist in the above-mentioned donepezil,
although not limited thereto and any form of crystal may exist
alone or in combination.
[0178] According to the present invention, the above-mentioned
compound may have an asymmetric carbon depending on the type of
substituent and may have an enantiomer, which are within the scope
of the present invention.
[0179] In one specific example, if J has an indanone skeleton
associated with an asymmetric carbon, a geometric isomer, an
enantiomer, a diastereomer or the like may exist. All of These
Cases are Within the Scope of the Present Invention.
[0180] 2. Therapeutic agent for overactive bladder involved in
aging
[0181] According to the present invention, a therapeutic agent for
overactive bladder involved in aging refers to a drug that
increases a bladder capacity that has decreased with aging of the
bladder in human or organisms other than human such as non-human
mammals including cow, monkey, avian, cat, mouse, rat, guinea pig,
hamster, pig, dog and rabbit. The therapeutic agent of the present
invention activates Ch nervous system in the brain by inhibiting
cholinesterase (ChE) (including acetylcholinesterase (AChE)) to
ameliorate overactive bladder such as urinary urgency, urinary
frequency and urinary incontinence. This means that the therapeutic
agent of the present invention is effective in improving
deterioration of overactive bladder and bladder capacity caused by
deterioration of functions involved in aging such as deterioration
of cholinergic neural action, preferably deterioration of central
cholinergic neural action, or deterioration of action of choline
acetyltransferase, i.e., ACh-synthesis enzyme, in the central
nerve. Thus, the therapeutic agent of the present invention may
effectively be used for treating overactive bladder in a patient
whose cholinergic neural action has deteriorated with aging, for
example, elderly person, Alzheimer's disease patient and
Parkinson's disease patient. The therapeutic agent of the present
invention desirably has no influence on micturition concentration
pressure, and is not associated with urge of urination. Also, the
therapeutic agent of the present invention may be termed either as
a therapeutic agent or an improving agent for urinary urgency,
urinary frequency, urinary incontinence and the like involved in
aging.
[0182] The compound having a ChE inhibitory activity described
above, a pharmacologically acceptable salt or a solvate thereof
increases the bladder capacity. In addition, they are useful as an
active ingredient of a therapeutic agent of the present
invention.
[0183] Thus, the present invention also provides a method for
treating overactive bladder involved in aging, comprising
administering an effective amount of the compound having a ChE
inhibitory activity described above, a pharmacologically acceptable
salt or a solvate thereof to a patient.
[0184] The term "treatment" generally means an achievement of a
desirable pharmacological effect and/or physiological effect. These
effects can be prophylactic in terms of completely or partially
preventing a disease and/or symptoms, and therapeutic in terms of
partially or completely curing a disease and/or adverse effects
caused by a disease. Herein, "treatment" refers to any treatment
for a disease of a mammal, particularly human, and also includes
general treatment as described above. "Treatment" includes, for
example, the following (a) to (c):
[0185] (a) to prevent a disease or a symptom in a patient who is
predisposed to the disease or the symptom but not yet diagnosed to
be so;
[0186] (b) to inhibit a disease or a symptom, that is, to stop or
delay the progress thereof;
[0187] (c) to alleviate a disease or a symptom, that is, to delay
or eliminate the disease or the symptom, or to reverse the progress
of the symptom.
[0188] A compound with a ChE inhibitory activity, a salt or a
solvate thereof, or a prodrug thereof, a salt or a solvate thereof
may be administered either orally or parenterally to a human or
non-human mammal (e.g., intravenous injection, muscle injection,
subcutaneous injection, rectal administration, transdermal
administration) by any one of various means. A compound having a
ChE inhibitory activity, a salt or a solvate thereof, or a prodrug
thereof, a salt or a solvate thereof may be used alone or may be
formulated into an appropriate formulation using a pharmaceutical
carrier by employing a conventionally used method depending on the
administration route.
[0189] Examples of preferable formulations include, for example,
oral formulations such as tablets, powder, fine granules, granules,
coated tablets, capsules, syrup and lozenge, and parenteral
formulations such as inhalers, suppositories, injectable agents
(including intravenous fluids), ointments, ophthalmic drops,
ophthalmic ointments, nasal drops, ear drops, adhesive patches,
skin pads, lotion and liposome formulations.
[0190] Examples of carriers that can be used for formulating these
formulations include, for example, a generally used solvent,
excipient, coating agent, binder, disintegrating agent, lubricant,
colorant, flavoring or aromatic substance, and if necessary, a
stabilizer, an emulsifying agent, an absorption promoter, a
surfactant, a pH regulator, an antiseptics, an antioxidant, a
filler, a wetting agent, a surface-active agent, a dispersant, a
buffer, a preservative, a solubilizing agent, a suspending agent, a
thickening agent, a soothing agent and a tonicity agent, which can
be formulated according to a common procedure by blending materials
generally used for formulating a medicinal formulation. Examples of
such non-toxic materials available include, for example, animal and
vegetable oils such as soybean oil, beef tallow and synthetic
glyceride; for example, hydrocarbons such as liquid paraffin,
squalane and solid paraffin; for example, ester oils such as
octyldodecyl myristate and isopropyl myristate; for example, higher
alcohols such as cetostearyl alcohol and behenyl alcohol; silicon
resin; silicon oil; for example, surfactants such as
polyoxyethylene fatty acid ester, sorbitan fatty acid ester,
glycerine fatty acid ester, polyoxyethylene sorbitan fatty acid
ester, polyoxyethylene hardened caster oil and
polyoxyethylene-polyoxypropylene block copolymer; for example,
water-soluble polymers such as hydroxyethylcellulose, polyacrylic
acid, carboxy vinyl polymer, polyethylene glycol, polyvinyl
pyrrolidone and methylcellulose; for example, lower alcohols such
as ethanol and isopropanol; for example, polyol such as glycerine,
propylene glycol, dipropylene glycol, sorbitol and polyethylene
glycol; for example, saccharides such as glucose and sucrose; for
example, inorganic powers such as anhydrous silicon, magnesium
aluminum silicate and aluminum silicate; inorganic salts such as
sodium chloride and sodium phosphate; and purified water.
[0191] Examples of excipients include, for example, lactose,
fructose, cornstarch, white sugar, glucose, mannitol, sorbit,
crystalline cellulose and silicon dioxide; examples of binders
include, for example, polyvinyl alcohol, polyvinyl ether,
methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin,
shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinyl pyrrolidone, polypropyleneglycol polyoxyethylene block
copolymer and meglumine; examples of disintegrating agents include,
for example, starch, agar, gelatin powder, crystalline cellulose,
calcium carbonate, sodium hydrogen carbonate, calcium citrate,
dextrin, pectin and sodium carboxymethylcellulose; examples of
lubricants include, for example, magnesium stearate, talc,
polyethylene glycol, silica and hardened plant oil; examples of
colorants include pharmaceutically acceptable additives; and
examples of flavoring or aromatic substances include cocoa powder,
menthol, aromatic powder, mint oil, borneol and cinnamon powder.
The materials mentioned above may be salts or solvates thereof.
[0192] An oral formulation is produced, for example, into powder,
fine granule, granule, a tablet, a coated tablet, a capsule or the
like obtained according to a routine procedure after adding an
excipient, and if necessary, further a binder, a disintegrating
agent, a lubricant, a colorant, a flavoring or aromatic substance
or the like to a compound having a ChE inhibitory activity, a salt
or a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof.
[0193] Tablets and granules may be coated according to a well-known
method using a coating agent such as carnauba wax,
hydroxypropylmethylcellulose, macrogol, hydroxypropylmethyl
phthalate, cellulose acetate phthalate, white sugar, titanium
oxide, sorbitan fatty acid ester or calcium phosphate.
[0194] Specific examples of carrier used for producing a syrup
agent include sweetening agents such as white sugar, glucose and
fructose, suspending agents such as gum arabic, tragacanth,
carmellose sodium, methylcellulose, sodium alginate, crystalline
cellulose and veegum, and dispersants such as sorbitan fatty acid
ester, sodium lauryl sulphate and polysorbate 80. For production of
syrup, a flavoring material, an aromatic material, a preservative,
a solubilizing agent and a stabilizer can be added as may be
necessary. The product may be in a form of dry syrup that can be
dissolved or suspended upon use.
[0195] An injectable agent is generally prepared by dissolving, for
example, a salt of a compound having a ChE inhibitory activity in
injectable distilled water, and may be formulated according to a
common procedure by adding a solubilizing agent, a buffer, a pH
regulator, a tonicity agent, a soothing agent, an antiseptic, a
preservative, a stabilizer or the like as may be necessary.
[0196] The injectable agent may be asepticized by filter
sterilization using a filter or by addition of a disinfectant. The
injectable agent may be produced into a form that can be prepared
upon use. Specifically, the injectable agent may be prepared into a
sterile solid composition by lyophilization or the like which can
be dissolved in sterile injectable distilled water or other solvent
before use.
[0197] Production of an external medicine is not limited to a
particular production procedure and may be produced by any routine
procedure. Various materials generally used in pharmaceuticals,
medicated cosmetics, cosmetics or the like may be used as a base
material. For example, materials such as animal or plant oil,
mineral oil, ester oil, wax, higher alcohols, fatty acids, silicon
oil, surfactant, phospholipids, alcohols, polyols, water-soluble
polymers, clay minerals, purified water or the like, and if
necessary, a pH regulator, an antioxidant, a chelating agent, an
antiseptic, a fungicide, a colorant, an aromatic substance or the
like may also be added. As to an inhaler, a compound having a ChE
inhibitory activity, a salt or a solvent thereof, or a prodrug
thereof or a salt or a solvent thereof can be delivered with an
injector, a nebulizer, a pressurized package or other means
suitable for delivering aerosol spray for inhalation
administration. The pressurized package may contain an appropriate
propellant. Moreover, for inhalation administration, a compound
having a ChE inhibitory activity, a salt or a solvate thereof, or a
prodrug thereof, a salt or a solvate thereof may be administered in
a form of dry powdered composition or liquid spray. For
administration with an adhesive patch via transdermal absorption,
it is preferable to select a so-called free-form that does not form
salt. For topical application to skin, a compound having a ChE
inhibitory activity may be formulated into ointment, cream or
lotion or as an active ingredient in a transdermal patch. Ointment
and cream can be formulated, for example, by adding an appropriate
thickening agent and/or gelling agent to an aqueous or oil base.
Lotion can be formulated by using an aqueous or oil base and may
generally contain one or more of an emulsifying agent, a
stabilizer, a dispersant, a suspending agent, a thickening agent
and/or a colorant. The compound having a ChE inhibitory activity
may also be administered by ion transfer therapy.
[0198] If necessary, components such as a blood circulating agent,
a disinfectant, an anti-inflammatory agent, a cellular stimulant,
vitamins, amino acids, a moisturizing agent, a keratolytic agent
may further be blended. The proportion of the active principle to
the carrier varies between 1 to 90% by weight.
[0199] The overactive bladder therapeutic agent used in the method
of the present invention can generally include, as an active
ingredient, a compound having a ChE inhibitory activity, a salt or
a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof at a proportion of 0.5% by weight or more, preferably 10 to
70% by weight.
[0200] When the compound having a ChE inhibitory activity, a salt
or a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof is used for the treatment described above, it is purified
for at least 90% or more, preferably 95% or more, more preferably
98% or more, still more preferably 99% or more.
[0201] A dose of the compound having a ChE inhibitory activity, a
salt or a solvate thereof, or a prodrug thereof, a salt or a
solvate thereof for oral administration varies as it is determined
according to multiple factors including, for example,
administration route, type of disease, degree of symptom, patient's
age, sex and weight, type of salt, specific type of disease,
pharmacological aspects such as pharmacokinetics and toxicological
features, use of drug delivery system, and whether it is
administered concomitantly with other drugs, but one skilled in the
art will be able to determine appropriately. For example, for an
adult (60 kg), about 0.001 to 1000 mg/day, preferably about 0.01 to
500 mg/day, and more preferably about 0.1 to 300 mg/day can be
administered at one time or in several times. When administered to
a child, a dose is possibly lower than that for an adult. The
administration procedure actually used may widely vary and can
depart from the preferable administration procedures described
herein. For example, in the case of donepezil hydrochloride,
preferably about 0.1 to 300 mg/day, more preferably about 0.1 to
100 mg/day, and still more preferably about 1.0 to 50 mg/day can be
administered to an adult (weight 60 kg). In a preferred embodiment
of donepezil hydrochloride, a 5 mg or 10 mg donepezil hydrochloride
tablet commercially available under the trade name of Aricept
tablet (Eisai Co., Ltd.), or donepezil hydrochloride under the
trade name of Aricept fine granule (Eisai Co., Ltd.) can be
administered. For example, tablets may be administered 1 to about 4
times a day. In a preferred embodiment, a 5 mg or 10 mg Aricept
tablet (Eisai Co., Ltd.) is administered once a day. Those skilled
in the art will appreciate that when donepezil hydrochloride is
administered to a child, the dose thereof is possibly lower than
that for an adult. In a preferred embodiment, donepezil
hydrochloride can be administered to a child for about 0.5 to 10
mg/day, preferably about 1.0 to 3 mg/day. Preferably, in the case
of Tacrine, about 0.1 to 300 mg/day, preferably about 40 to 120
mg/day is administered to an adult (weight 60 kg); in the case of
Rivastigmine, about 0.1 to 300 mg/day, preferably about 3 to 12
mg/day is administered to an adult (weight 60 kg); in the case of
galantamine, about 0.1 to 300 mg/day, preferably about 16 to 32
mg/day is administered to an adult (weight 60 kg); and in the case
of physostigmine, about 0.1 to 300 mg/day, preferably about 0.6 to
24 mg/day is administered to an adult (weight 60 kg). For each of
the above cases, a dose to a child may possibly be lower than that
for an adult.
[0202] As to parenteral administration, a preferable dose for
adhesive patch would be about 5 to 50 mg/day, more preferably about
10 to 20 mg/day for an adult (60 kg). An injectable agent may be
produced by dissolving or suspending it in a pharmacologically
acceptable carrier such as saline or a commercially available
injectable distilled water to a concentration of 0.1 .mu.g/ml
carrier to 10 mg/ml carrier. A dose of such an injectable agent to
a patient in need of the treatment may be about 0.01 to 50 mg/day,
preferably about 0.01 to 5.0 mg/day, more preferably about 0.1 to
1.0 mg/day for an adult (60 kg), and may be administered 1 to 3
times a day. When administered to a child, the dose may possibly be
lower than that for an adult.
[0203] 3. Process for Screening Substance for Suppressing
Overactive Bladder Involved in Aging, Pharmacologically Acceptable
Salt or Solvate Thereof
[0204] The present invention further provides a process for
screening a substance that suppresses overactive bladder involved
in aging, a pharmacologically acceptable salt or a solvate
thereof.
[0205] A screening process according to the present invention
comprises administrating a candidate substance to a non-human
mammal, and detecting or determining a change in a phenotype of
overactive bladder involved in aging in the presence and absence of
the candidate substance.
[0206] Herein, "in the presence" means that the candidate substance
has been administered to a non-human animal, and "in the absence"
means that the candidate substance has not been administered to a
non-human animal. Thus, upon screening, individuals from a
non-human animal group administered with the candidate substance
are compared with individuals from a control non-human animal group
not administered with the candidate substance to detect or
determine the phenotypes. Alternatively, a phenotype of an
individual prior to administration of a candidate substance may be
compared with a phenotype of the same individual administered with
the candidate substance.
[0207] According to the screening process of the present invention,
the candidate substance include a substance having an ChE
(including AChE) inhibitory activity, for example, the compound
having a ChE inhibitory activity described above, an anti-ChE
antibody, siRNA and shRNA to ChE and the like. The substance may be
a salt or a solvate of the above. The compound having a ChE
inhibitory activity can be produced or obtained by referring to the
description above. The anti--ChE antibody may be either a
monoclonal antibody or a polyclonal antibody, and those skilled in
the art would be able to produce such antibodies, for example, by
using ChE as a sensitized antigen. siRNA or shRNA for ChE gene may
be any nucleic acid that is capable of suppressing the expression
of ChE gene, and those skilled in the art would be able to
appropriately design a sequence and produce siRNA or shRNA
(Elbashir, S.M., et. al., Genes Dev., 15, 188-200, 2001).
[0208] A candidate compound may be administered to a non-human
mammal either orally or parenterally.
[0209] A change in a phenotype of overactive bladder involved in
aging may use at least one of a bladder capacity, a bladder
contraction pressure and an amount of retained urine as an index.
The substance can be determined to be suppressive to overactive
bladder involved in aging when at least one of the following (a) to
(c) applies:
[0210] (a) when the substance increases bladder capacity,
[0211] (b) when the substance prevents bladder contraction pressure
from decreasing, or
[0212] (c) when the substance prevents retained urine from
increasing.
[0213] In order to detect or determine the change in a phenotype of
the overactive bladder involved in aging, a pressure within the
bladder is determined, preferably a pressure within the non-human
mammal bladder in a waking state is determined.
[0214] The present invention further provides a kit for screening a
substance capable of suppressing overactive bladder involved in
aging, a pharmacologically acceptable salt or a solvate thereof
which are to be used in the method described above. The screening
kit of the invention includes means required for determining a
change in a phenotype of overactive bladder involved in aging.
Agents suitably used upon determining the phenotype change are
general anesthetics (e.g., halothane) and saline. The screening kit
of the present invention may further include an instruction, a
tube, a flask or the like.
EXAMPLES
[0215] Hereinafter, the present invention will be described more
specifically by way of non-limiting examples.
Example 1
Production of Donepezil Hydrochloride
[0216] (a) Synthesis of 1-benzyl-4-piperidine carboaldehyde
##STR80##
[0217] 26.0 g of methoxymethylenetriphenylphosphonium chloride was
suspended in 200 ml anhydrous ether, and 1.6 M n-butyllithiumhexane
solution was added dropwise at room temperature. After stirring at
room temperature for 30 minutes, the resultant was cooled to
0.degree. C., and 14.35 g 1-benzyl-4-piperidone in 30 ml anhydrous
ether solution was added. After stirring at room temperature for 3
hours, insoluble matter was filtered out and the filtrate was
concentrated under reduced pressure. The obtained residue was
dissolved in ether and extracted with IN hydrochloric acid.
Following adjustment of pH to 12 with sodium hydroxide solution,
the resultant was extracted with methylene chloride. The resultant
was dried with magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified through a silica gel
column, thereby obtaining 5.50 g of oily substance (yield 33%).
[0218] Subsequently, the obtained oily substance was dissolved in
40 ml methanol, and added with 40 ml 1N hydrochloric acid. The
reaction solution was heated to reflux for 3 hours, then
concentrated under reduced pressure. The residue was dissolved in
water. Thereafter, pH of the dissolved solution was adjusted to 12
with sodium hydroxide solution, and extracted with methylene
chloride. The extracted solution was washed with saturated saline,
dried with magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified through a silica gel
column to obtain 2.77 g of 1-benzyl-4-piperidinecarboaldehyde
(yield 54%) as an oily substance.
[0219] The structure of the obtained compound was determined by
NMR.
[0220] Molecular formula; C.sub.13H.sub.17NO.sup.1H-NMR
(CDCl.sub.3).delta.; 1.40-2.40 (7H, m), 2.78 (2H, dt), 3.45 (2H,
s), 7.20 (5H, s), 9.51 (1H, d).
[0221] (b) Synthesis of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine
hydrochloride (formula below) ##STR81##
[0222] This reaction took place in argon atmosphere.
[0223] 2.05 ml diisopropylamine was added to 10 ml anhydrous THF
and 9.12 ml 1.6M n-butyllithium hexane solution was further added
at 0.degree. C. The resultant was stirred at 0.degree. C. for 10
minutes, cooled to -78.degree. C., and added with 2.55 g
5,6-dimethoxy-1-indanone in 30 ml anhydrous THF solution and 2.31
ml hexamethyl phosphoramide. The resultant was stirred at
-78.degree. C. for 15 minutes, added with 2.70 g
1-benzyl-4-piperidinecarboaldehyde obtained in (a) in 30 ml
anhydrous THF solution, and gradually heated to room temperature.
Again stirring at room temperature for another 2 hours, 1% ammonium
chloride solution was added to separate the organic layer. Next,
the aqueous layer was extracted with ethyl acetate, combined with
the organic layer separated above, and washed with saturated
saline. The solution was dried with magnesium sulfate, concentrated
under reduced pressure, and the obtained residue was purified
through a silica gel column (methylene chloride: methanol
.dbd.500:1 to 100:1). After concentrating the eluate under reduced
pressure, the resultant was dissolved in methylene chloride, added
with 10% hydrochloric acid-ethyl acetate solution, and further
concentrated under reduced pressure to obtain a crystal. This was
recrystallized from methylene chloride-IPE to obtain 3.40 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine
hydrochloride (yield 62%) having the following properties: [0224]
Melting point (.degree. C.); 237-238 (dec.) [0225] Elementary
analysis; as C.sub.24H.sub.27NO.sub.3 HCl, CHN calculated (%):
69.64 6.82 3.38, found (%): 69.51 6.78 3.30.
[0226] (c)
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride ##STR82##
[0227] 0.40 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine
obtained in (b) was dissolved in 16 ml THF, and 0.04 g of 10%
palladium-carbon was added. After hydrogenating under atmospheric
pressure at room temperature for 6 hours, catalyst was filtered
out, and the filtrate was concentrated under reduced pressure. The
residue was purified through a silica gel column (methylene
chloride: methanol.dbd.50:1), and the eluate was concentrated under
reduced pressure. Thereafter, the residue was dissolved in
methylene chloride, added with 10% hydrochloric acid-ethyl acetate
solution, and was further concentrated under reduced pressure,
thereby obtaining a crystal. This was recrystallized from
ethanol-IPE to obtain 0.36 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride (donepezil hydrochloride) (yield 82%) having the
following properties: [0228] Melting point (.degree. C.); 211-212
(dec.) [0229] Elementary analysis; as C.sub.24H.sub.29NO.sub.3 HCl,
CHN calculated (%): 69.30 7.27 3.37, found (%): 69.33 7.15
3.22.
Example 2
Experiments with Aged Rat
[0230] After conducting cystostomy on and intravenously
administering 5.times.10.sup.-5 mg/ml donepezil hydrochloride to
3-week-old, 10-week-old and 10-month-old female Wistar rats, the
bladder capacity was determined as measured by pressure within the
bladder.
[0231] The results are shown in FIG. 1. An increase in the bladder
capacities were seen in the 10-week-old and 10-month-old rats by
administration of donepezil hydrochloride. Particularly in the
10-month-old rat, donepezil hydrochloride as a central
cholinesterase inhibitor was found to increase the bladder capacity
by 60% (FIG. 1).
Example 3
[0232] Aging in human is reported to deteriorate the function of
acetylcholine system in brain. Deterioration in the acetylcholine
system involved in aging is also suggested to cause disorder of the
lower urinary tract function.
[0233] Thus, in this example, donepezil hydrochloride as a central
cholinesterase inhibitor was administered to examine the change in
the bladder function using aged rats.
[0234] Materials and Methods
[0235] 8 week-old, 12 month-old and 24 month-old female S-D rats
were used.
[0236] After the rats were subjected to cystostomy under anesthesia
of 1.5% halothane and restrained in Bollman cages, pressure within
the bladder was determined in a waking state. Thereafter,
5.times.10.sup.-5 mg/kg of donepezil hydrochloride were
administered transvenously and the pressure within the bladder was
determined.
[0237] The rats used were as follows: TABLE-US-00001 Five
8-week-old rats average weight 172 g Four 12-month-old rats average
weight 350 g Four 24-month-old rats average weight 430 g.
[0238] Results
[0239] FIG. 2 shows an exemplary change in the curve of pressure
within the bladder when donepezil hydrochloride was administered to
500 g 12-month-old rats. By administration of donepezil
hydrochloride, the bladder capacity increased by 132%.
[0240] FIG. 3 shows percentage of change in the bladder capacity by
donepezil hydrochloride. The percentage of change were -6.4%, 40.3%
and 93% for 8-week-old, 12-month-old and 24-month-old rats,
respectively, and bladder capacity significantly increased in the
24-month-old rat than the 8-week-old rat (p=0.0139).
[0241] FIG. 4 shows percentage of change in micturition
concentration pressure. There was no significant difference in the
micturition concentration pressure among the three groups, i.e.,
the 8-week-old, 12-month-old and 24-month-old rats.
[0242] In summary, administration of donepezil hydrochloride to the
8 week-old, 12 month-old and 24 month-old rats resulted in an
increase in the percentage of change in the bladder capacity with
aging. The percentage of change significantly increased in the
24-month-old rats than the 8-week-old rat. Thus, it was considered
that suppressive projection of the acetylcholine system in the
brain was also attenuated in aged rats, and therefore the
administration of donepezil hydrochloride that activates ACh system
selectively to brain increased the bladder capacity.
INDUSTRIAL APPLICABILITY
[0243] The present invention provides a therapeutic agent for
overactive bladder involved in aging comprising, as an active
ingredient, a compound having a cholinesterase (ChE) inhibitory
activity or a pharmacologically acceptable salt thereof. An
overactive bladder therapeutic agent of the invention is useful as
a novel therapeutic agent for urine collection disorder associated
with overactive bladder involved in aging. The compound of the
invention, for example, donepezil hydrochloride, has no side
effects such as dry mouth, constipation and urinary excretion
disorder which accompany the existing overactive bladder
therapeutic agents. In addition, considering that most of the
patients to be administered are elderly, donepezil hydrochloride
can be administered safely without being concerned about damage in
higher brain functions, and thus can be a innovative therapeutic
agent for overactive bladder involved in aging.
* * * * *